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Fantastic voyage: The journey of NLRP3 inflammasome activation

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Genes & Diseases 2024年第2期11卷 819-829页

作者： Xiangyong Que Sihao Zheng Qibin Song Huadong Pei Pingfeng Zhang cancer center Renmin Hospital of Wuhan UniversityWuhanHubei 430060China Department of Oncology Georgetown Lombardi Comprehensive Cancer CenterGeorgetown University Medical CenterWashingtonDC 20057USA

NLRP3 inflammasome,an intracellular multiprotein complex,can be activated by a range of pathogenic microbes or endogenous hazardous *** activation results in the release of cytokines such as IL-1β and IL-18,as well as Gasdermin D which eventually causes *** activation of NLRP3 inflammasome is under strict control and regulation by numerous pathways and *** excessive activation can lead to a persistent inflammatory response,which is linked to the onset and progression of severe *** studies have revealed that the subcellular localization of NLRP3 changes significantly during the activation *** this review,we review the current understanding of the molecular mechanism of NLRP3 inflammasome activation,focusing on the subcellular localization of NLRP3 and the associated regulatory *** aim to provide a comprehensive understanding of the dynamic transportation,activation,and degradation processes of NLRP3.

关键词： Inflammasome activation Innate immunity NLRP3 NLRP3 inflammasome Subcellular localization

CD8+T cell metabolic flexibility elicited by CD28-ARS2 axisdriven alternative splicing of PKM supports antitumor immunity

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Cellular & Molecular Immunology 2024年第3期21卷 260-274页

作者： G.Aaron Holling Colin A.Chavel Anand P.Sharda Mackenzie M.Lieberman Caitlin M.James Shivana M.Lightman Jason H.Tong Guanxi Qiao Tiffany R.Emmons Thejaswini Giridharan Shengqi Hou Andrew M.Intlekofer Richard M.Higashi Teresa W.M.Fan Andrew N.Lane Kevin H.Eng Brahm H.Segal Elizabeth A.Repasky Kelvin P.Lee Scott H.Olejniczak Department of Immunology Roswell Park Comprehensive Cancer CenterBuffaloNY 14263USA Department of Medicine Roswell Park Comprehensive Cancer CenterBuffaloNY 14263USA Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer CenterNew YorkNY 10065USA center for Environmental Systems Biochemistry Department of Toxicology and Cancer Biology and Markey Cancer CenterLexingtonKY 40536USA Department of cancer Genetics and Genomics Roswell Park Comprehensive Cancer CenterBuffaloNY 14263USA Present address:university of Colorado Boulder BoulderCO 80309USA Present address:Dana Farber cancer Institute BostonMA 02215USA Present address:Massachusetts Institute of Technology BostonMA 02139USA Present address:Melvin and Bren Simon comprehensive cancer center Indiana University School of MedicineIndianapolisIN 46202USA

Metabolic flexibility has emerged as a critical determinant of CD8+T-cell antitumor activity,yet the mechanisms driving the metabolic flexibility of T cells have not been *** this study,we investigated the influence of the nuclear cap-binding complex(CBC)adaptor protein ARS2 on mature T *** doing so,we discovered a novel signaling axis that endows activated CD8+T cells with flexibility of glucose ***2 upregulation driven by CD28 signaling reinforced splicing factor recruitment to pre-mRNAs and affected approximately one-third of T-cell activation-induced alternative splicing *** these effects,the CD28-ARS2 axis suppressed the expression of the M1 isoform of pyruvate kinase in favor of PKM2,a key determinant of CD8+T-cell glucose utilization,interferon gamma production,and antitumor effector ***,PKM alternative splicing occurred independently of CD28-driven PI3K pathway activation,revealing a novel means by which costimulation reprograms glucose metabolism in CD8+T cells.

关键词： Immunometabolism mRNA splicing CD8 T cells ARS2 PKM2

Emerging mechanisms of ferroptosis and its implications in lung cancer

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Chinese Medical Journal 2024年第7期137卷 818-829页

作者： Qian Li Qibin Song Huadong Pei Yali Chen cancer center Renmin Hospital of Wuhan UniversityWuhanHubei 430060China Department of Oncology Georgetown Lombardi Comprehensive Cancer CenterGeorgetown University Medical CenterWashington D.C.20057USA State Key Laboratory of Medical Proteomics National Center for Protein Sciences(Beijing)Beijing Institute of LifeomicsBeijing 102206China

Lung cancer is one of the most common malignancies and has the highest number of deaths among all *** continuous advances in medical strategies,the overall survival of lung cancer patients is still low,probably due to disease progression or drug *** is an iron-dependent form of regulated cell death triggered by the lethal accumulation of lipid peroxides,and its dysregulation is implicated in cancer *** evidence has shown that targeting the ferroptosis pathway could be a potential strategy for improving lung cancer treatment *** this review,we summarize the underlying mechanisms and regulatory networks of ferroptosis in lung cancer and highlight ferroptosis-targeting preclinical attempts to provide new insights for lung cancer treatment.

关键词： Lung cancer Ferroptosis Ferroptosis regulators Ferroptosis inducers cancer treatment

The impact of broad glutamine metabolism inhibition on the tumor microenvironment

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Genes & Diseases 2024年第3期11卷 2-4页

作者： Tianhe Li Yun-Ta Chuang Tian-Li Wang Departments of Pathology Oncologyand Gynecology and ObstetricsThe Sidney Kimmel Comprehensive Cancer CenterJohns Hopkins University School of MedicineBaltimoreMD 21231USA

Glutamine is an importantα-amino acid that provides carbon and nitrogen sources for the biosynthesis of nucleotides,proteins,and *** also generates metabolites that fuel the tricarboxylic acid cycle and maintain intracellular redox *** cells have a heightened metabolic dependence on glutamine to support incessant tumor growth and mitigate tumor microenvironmental stresses including hypoxia,nutrient depletion.

关键词： metabolism tumor microenvironment

Mechanism of PARP inhibitor resistance and potential overcoming strategies

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Genes & Diseases 2024年第1期11卷 306-320页

作者： Xiaoyu Fu Ping Li Qi Zhou Ruyuan He Guannan Wang Shiya Zhu Amir Bagheri Gary Kupfer Huadong Pei Juanjuan Li Department of Oncology Georgetown Lombardi Comprehensive Cancer CenterGeorgetown University Medical CenterWashingtonDC 20057USA Department of Breast and Thyroid Surgery Renmin Hospital of Wuhan UniversityWuhanHubei 430060China cancer center Renmin Hospital of Wuhan UniversityWuhanHubei 430060China Department of Thoracic Surgery Renmin Hospital of Wuhan UniversityWuhanHubei 430060China

PARP inhibitors(PARPi)are a kind of cancer therapy that targets poly(ADP-ribose)*** is the first clinically approved drug to exert synthetic lethality by obstruct-ing the DNA single-strand break repair *** the significant therapeutic effect in pa-tients with homologous recombination(HR)repair deficiency,innate and acquired resistance to PARPi is a main challenge in the *** this review,we mainly discussed the underlying mechanisms of PARPi resistance and summarized the promising solutions to overcome PARPi resistance,aiming at extending PARPi application and improving patient outcomes.

关键词： Drug resistance Homologous recombination PARP PARP inhibitor Poly(ADP-ribose)polymerase

Recent advances in cancer-associated fibroblast:Biomarkers,signaling pathways,and therapeutic opportunities

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Chinese Medical Journal 2024年第6期137卷 638-650页

作者： Donger Zhou Lei Zheng Department of Hepatobiliary-Pancreatic Surgery The Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang 310009China Sidney Kimmel comprehensive cancer center The Skip Viragh Pancreatic Cancer Center for Clinical Research and Careand The Bloomberg-Kimmel Institute for Immunotherapy at Johns Hopkins University School of MedicineBaltimoreMD 21287USA

Anti-cancer therapies usually focus on tumor cells,but non-tumor stromal components in the tumor microenvironment also play vital roles in tumor initiation and progression,which may be the prognostic factors and potential therapeutic ***-associated fibroblasts(CAFs)are the essential component in the tumor environment,exhibiting high heterogeneity in their cell origin and phenotype with diverse functions that influence tumor angiogenesis,immune systems,and ***-cell RNA sequencing and genetically engineered mouse models have increased our understanding of CAF diversity,and many subtypes have been ***,the precise functions of these subtypes need to be studied and *** of signaling pathways and epigenetic changes in CAFs facilitate understanding of the phenotypes of CAFs and the crosstalk between tumor cells and CAFs to provide potential therapeutic *** clinical trials,including phase III trials targeting CAFs,have been performed ***,few of these trials have generated promising results,which indicates that the complexity of CAFs in the tumor microenvironment remains largely unknown,and in-depth investigations of CAFs should be *** review summarizes the research on CAFs,focusing on the heterogeneity of their phenotypes and functions,specific signaling pathways,and the therapeutic strategies involving ***,we briefly discuss the current technologies commonly used in CAF studies and describe the challenges and future perspectives of CAF research.

关键词： cancer-associated fibroblasts Tumor microenvironment Anti-cancer therapy Targeted therapy

Medical management of urolithiasis: Great efforts and limited progress

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Asian Journal of Urology 2024年第2期11卷 149-155页

作者： Victoria Jahrreiss Christian Seitz Fahad Quhal Department of Urology Comprehensive Cancer CenterMedical University of ViennaViennaAustria Department of Urology King Fahad Specialist HospitalDammamSaudi Arabia

Objective:To provide a comprehensive review on the existing literature on medical management of ***:A thorough literature review was performed using Medline,PubMed/PMC,Embase,and the Cochrane Database of Systematic Reviews up to December 2022 to identify publications on the medical management of *** that assessed dietary and pharmacologic management of urolithiasis were reviewed;studies on medical expulsive therapy were not included in this ***:Medical management of urolithiasis ranges from the prophylactic management of kidney stone disease to dissolution *** most treatment concepts have been long established,large randomized controlled trials are *** modification and increased fluid intake remain cornerstones in the conservative management of urolithiasis.A major limitation for medical management of urolithiasis is poor patient ***:Medical management of urolithiasis is more important in patients with recurrent urolithiasis and patients with metabolic abnormalities putting them at higher risk of developing *** medical management can be effective in limiting stone recurrence,medical interventions often fail due to poor compliance.

关键词： Medicalmanagement Medical therapy Urolithiasis Kidneystonedisease

Estrogen receptor beta suppresses the androgen receptor oncogenic effects in triple-negative breast cancer

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Chinese Medical Journal 2024年第3期137卷 338-349页

作者： Feng Xu Kun Xu Lingling Fan Xintong Li Yiqiu Liu Fang Yang Chengjun Zhu Xiaoxiang Guan Department of Oncology The First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu 210029China Department of Oncology Jiangsu Cancer HospitalThe Affiliated Cancer Hospital of Nanjing Medical UniversityJiangsu Institute of Cancer ResearchNanjingJiangsu 210009China The comprehensive cancer center of Nanjing Drum Tower Hospital Affiliated Hospital of Medical SchoolNanjing UniversityNanjingJiangsu 210008China Jiangsu Key Lab of cancer Biomarkers Prevention and TreatmentCollaborative Innovation Center for Personalized Cancer MedicineNanjing Medical UniversityNanjingJiangsu 211166China

Background:Triple-negative breast cancer(TNBC)is an aggressive type of breast cancer associated with poor prognosis and limited treatment *** androgen receptor(AR)has emerged as a potential therapeutic target for luminal androgen receptor(LAR)***,multiple studies have claimed that anti-androgen therapy for AR-positive TNBC only has limited clinical *** study aimed to investigate the role of AR in TNBC and its detailed ***:Immunohistochemistry and TNBC tissue sections were applied to investigate AR and nectin cell adhesion molecule 4(NECTIN4)expression in TNBC ***,in vitro and in vivo assays were used to explore the function of AR and estrogen receptor beta(ERβ)in *** immunoprecipitation sequencing(ChIP-seq),co-immunoprecipitation(co-IP),molecular docking method,and luciferase reporter assay were performed to identify key molecules that affect the function of ***:Based on the TNBC tissue array analysis,we revealed that ERβand AR were positive in 21.92%(32/146)and 24.66%(36/146)of 146 TNBC samples,respectively,and about 13.70%(20/146)of TNBC patients were ERβpositive and AR *** further demonstrated the pro-tumoral effects of AR on TNBC cells,however,the oncogenic biology was significantly suppressed when ERβtransfection in LAR TNBC cell lines but not in AR-negative ***,we identified that NECTIN4 promoter–42 bp to–28 bp was an AR response element,and that ERβinteracted with AR thus impeding the AR-mediated NECTIN4 transcription which promoted epithelial–mesenchymal transition in tumor ***:This study suggests that ERβfunctions as a suppressor mediating the effect of AR in TNBC prognosis and cell ***,our current research facilitates a better understanding of the role and mechanisms of AR in TNBC carcinogenesis.

关键词： Androgen receptor Estrogen receptor beta Triple-negative breast cancer NECTIN4 Oncogenic effects Tumor progression

Modularization of adhesion G protein-coupled receptor(aGPCR)structure:how alternative splicing regulates synaptogenesis

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Signal Transduction and Targeted Therapy 2024年第5期9卷 1793-1795页

作者： Tobias Langenhan Rudolf Schönheimer Institute of Biochemistry Division of General BiochemistryMedical FacultyLeipzig UniversityLeipzigGermany comprehensive cancer center Central Germany(CCCG) Leipzig UniversityLeipzigGermany Institute of Biology Faculty of Life SciencesLeipzig UniversityLeipzigGermany

A recent report has uncovered a fascinating aspect of how neurons utilize alternative splicing of transcripts of an adhesion G protein-coupled receptor(aGPCR)gene to serve specific functions in the life of a synapse.1 The work provides significant insight into the ability of cells to support distinct biochemical and physiological operations through post-transcriptional processing of genetic information that is encoded in a single aGPCR locus.

关键词： GPCR utilize operations